2-substituted 1,2-benzisothiazole derivatives and their use as serotonin antagonists (5-HT1A, 5HT1B and 5-HT1D)

ABSTRACT

where the substituents have the meanings indicated in the description, their preparation and use as serotonin antagonists.

The invention relates to 2-substituted 1,2-benzoisothiazole derivatives,their preparation and use for preparing active ingredients of drugs.

Classical antidepressants, and the newer selective serotonin reuptakeinhibitors (SSRIs) exert their antidepressant effect inter alia byinhibiting active reuptake of the transmitter into the presynaptic nerveendings. Unfortunately, in this case the antidepressant effect has itsonset only after treatment for at least 3 weeks, moreover, about 30% ofpatients are therapy-resistent.

Blockade of presynaptic serotonin autoreceptors increases, by abolishingnegative coupling, the serotonin release and thus the instantaneoustransmitter concentration in the synaptic cleft. This increase in thetransmitter concentration is regarded as the principle of theantidepressant effect. This mechanism of action differs from that ofpreviously disclosed antidepressants which activate both the presynapticand somatodendritic autoreceptors and therefore result in a delayedonset of action only after desensitization of these autoreceptors.Direct autoreceptor blockade bypasses this effect.

It is known that although the thiazole derivatives described in DE3620643 have affinity for 5-HT_(1A) receptors they have no 5-HT_(1B)affinity.

According to current knowledge, the presynaptic serotonin autoreceptoris of the 5-HT_(1B) subtype (Fink et al., Arch. Pharmacol. 352 (1995),451). Selective blockade thereof by 5-HT_(1B/D) antagonists increasesserotonin release in the brain: G. W. Price et al., Behavioural BrainResearch 73 (1996), 79-82; P. H. Hutson et al., Neuropharmacology Vol.34, No. 4 (1995), 383-392.

However, surprisingly, the selective 5-HT_(1B) antagonist GR 127 935reduces serotonin release in the cortex after systemic administration.One explanation might be stimulation of somatodendritic 5-HT_(1A)receptors in the raphe region by the released serotonin, which inhibitsthe rate of firing of serotonergic neurones and thus serotonin excretion(M. Skingle et al., Neuropharmacology Vol. 34, No. 4 (1995), 377-382,393-402).

One strategy for bypassing the autoinhibitory effects in serotonergicareas of origin thus aims at blockade of the presynaptic 5-HT1B [sic]receptors. This hypothesis is supported by the observation that theeffect of paroxetine on serotonin release in the dorsal raphe nucleus ofthe rat is potentiated by the 5-HT_(1B) receptor antagonist GR 127 935(Davidson and Stamford, Neuroscience Letts., 188 (1995),41).

The second strategy includes blockade of both types of autoreceptors,namely the 5-HT_(1A) receptors, in order to enhance neuronal firing, andthe 5-HT_(1B) receptors, in order to increase terminal serotonin release(Starkey and Skingle, Neuropharmacology 33 (3-4) (1994),393).

5-HT_(1B/D) antagonists, alone or coupled to a 5-HT_(1A) receptorantagonist component, ought therefore to cause a greater increase inserotonin release in the brain and might therefore entail advantages inthe therapy of depression and related psychological disorders.

It has now been found that 2-substituted 1,2-benzoisothiazolederivatives of the formula I

where

R¹ and R² are, independently of one another (C₁₋₆) alkyl,

R³ and R⁴ are, independently of one another, hydrogen, (C₁₋₆) alkylbranched or unbranched, OH, O—(C₁₋₆)-alkyl branched or unbranched, F,Cl, Br, I, trifluoromethyl, NR⁵R⁶, CO₂R⁷, nitro, cyano, pyrrole, aphenylalkyl C₁-C₄ radical which in turn can be substituted on thearomatic system by F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy,trifluoromethyl, hydroxyl, amino, cyano or nitro,

R⁵ and R⁶ are, independently of one another, hydrogen, (C₁₋₆) alkylbranched or unbranched, COPh, CO₂tBu, CO—(C₁₋₄)-alkyl or together are a5- or 6-membered ring which may contain a second nitrogen (e.g.piperazine),

R⁷ is hydrogen and (C₁₋₆) alkyl branched or unbranched,

A is branched or unbranched (C₁₋₁₀)-alkylene or straight-chain orbranched (C₂₋₁₀)-alkylene, which comprises at least one group Z which isselected from O, S, NR⁷, cyclopropyl, CHOH, a double or a triple bond,

B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine and thecorresponding cyclic compounds enlarged by one methylene group, thelinkage to A taking place by one nitrogen atom of B, and

Ar is phenyl which is unsubstituted or substituted by (C₁₋₆) alkylbranched or unbranched, O—(C₁₋₆)-alkyl branched or unbranched, OH, F,Cl, Br, I, trifluoromethyl, NR⁵R⁶, CO₂R⁷, cyano or phenyl or istetralin, indan, fused aromatic systems such as naphthalene which isunsubstituted or substituted by (C₁₋₄) alkyl or O(C₁₋₄) alkyl, oranthracene or 5- or 6-membered aromatic heterocycles having 1 or 2heteroatoms which are selected, independently of one another, from O andN and which may also be fused to other aromatic radicals, for examplequinoline, isoquinoline, phthalazine, indole and quinazoline, which inturn may be substituted by phenyl,

and their salts with physiologically tolerated acids, have valuablepharmacological properties.

Preferred compounds of the formula I are those where

R¹ and R² is [sic], independently of one another, methyl or ethyl,

R³ and R⁴ are, independently of one another, hydrogen, O—(C₁₋₄)-alkylbranched or unbranched, F, Cl, Br, trifluoromethyl, NR⁵R⁶, nitro, cyanoand phenyl,

R⁵ and R⁶ are, independently of one another, hydrogen, COPh, CO₂tBu,(C₁₋₆) alkyl branched or unbranched and CO—(C₁₋₄)-alkyl,

A is branched or unbranched (C₂₋₅) alkylene or straight-chain orbranched (C₂₋₅) alkylene, which comprises a group Z which is selectedfrom CHOH, cyclopropyl, a double or a triple bond,

B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine orhomopiperazine, the linkage to A taking place by one nitrogen atom of B,and

Ar is phenyl which is unsubstituted or substituted by (C₁₋₆) alkylbranched or unbranched, O—(C₁₋₆)-alkyl branched or unbranched, F, Cl,Br, I, trifluoromethyl, NR⁵R⁶, CO₂R⁷, cyano and phenyl, or tetralin,indan, fused aromatic systems such as naphthalene which is unsubstitutedor substituted by (C₁₋₄) alkyl or O(C₁₋₄) alkyl, or anthracene and 5- or6-membered aromatic heterocycles having 1 or 2 heteroatoms which areselected, independently of one another, from O and N, and which may befused to other aromatic radicals.

Particularly preferred compounds of the formula I are the compoundslisted in claim 3.

The compounds of the formula I may have one or more centers ofasymmetry. The invention therefore includes not only the racemates butalso the relevant enantiomers and diastereomers. The invention alsoincludes the respective tautomeric forms.

The novel compounds of the formula I can be prepared by reacting acompound of the formula II

where R¹ to R⁴ and A have the meanings stated above, and Q is a groupwhich can be eliminated (e.g. Cl, Br, I, alkanesulfonyloxy orarylsulfonyloxy), with a secondary amine of the formula III,

H—B—Ar  III

where B and Ar have the meanings stated above, in a manner known per se,and converting the compound obtained in this way where appropriate intothe addition salt with a physiologically tolerated acid. It is likewisepossible to react a compound of the formula IV

with a compound of the formula V

Q—A—B—Ar  V

in a manner known per se. Another synthetic variant is linkage of acompound of the formula VI

to a compound of the formula III by a reductive amination known per se.

Compounds of the formula III can be synthesized by

1. linking compounds of the formula VII

W—B¹  (VII)

 where B¹ is piperazine or homopiperazine and W is hydrogen or one ofthe usual amino protective groups (e.g. Boc or Cbz), with a compound ofthe formula VIII

P—Ar  (VIII),

 where P is B(OH)₂, SnR₃, OTf, Br, Cl, or I and R is C₁-C₄-alkyl, in aknown manner; or

2. linking compounds of the formula IX

W—B²—P¹  (IX)

 where B² is 4-tetrahydro-1,2,3,6-pyridine and the corresponding cycliccompounds enlarged by one methylene group, and P¹ is Cl, Br, I, SnR₃,where R is C₁-C₄-alkyl, or OTf to a compound of the formula X

P—Ar  (X)

 where W, P and Ar each have the abovementioned meanings, and thereactions are carried out by known processes as described, for example,in

S. L. Buchwald et al. J. Am. Chem. Soc. 1996, 118, 7215

J. F. Hartwig et al. Tetrahedron Lett. 1995, 36, 3604

J. K. Stille et al. Angew. Chem. 1986, 98, 504

S. L. Buchwald et al. Angew. Chem. 1995, 107, 1456 or J. F.

J. F. Hartwig et al. J.Am. Chem. Soc 1996, 118, 7217 or

J. F. Hartwig et al. J.Org. Chem. 1997, 62, 1268

S. L. Buchwald et al. J.Org. Chem. 1997, 62, 1264 and literature citedtherein or

S. L. Buchwald et al J.Am. Chem. Soc 1997, 119, 6054

J. K. Stille, Angew. Chem. 1986, 98, 504 or

J. K. Stille et al. J.Org.Chem. 1990, 55, 3014.

M. Pereyre et al. “Tin in Organic Synthesis”, Butterworth 1987; or

3. reducing compounds of the formula (XI)

W—B²—Ar  XI

 where B² has the meaning stated above, to compounds of the formula XII

W—B³—Ar  (XII)

 where B³ is piperidines linked in the 1,4 positions and thecorresponding cyclic compounds enlarged by one methylene group, or

4. cyclizing compounds of the formula XIII

W—N—(C₂H₄Q)₂  (XIII),

 where W and Q have the meanings described above, with a compound of theformula XIV

NH₂—Ar  (XIV),

 where Ar has the abovementioned meaning, to give compounds of theformula XV

W—B¹—Ar  (XV).

The substances of the formulae III and V required as starting materialsfor synthesizing the novel compounds are known or can be synthesized byknown processes (e.g. Organikum Barth Dt. Verl. der Wiss. 1993 or A. R.Katritzky, C. W. Rees (ed.) Comprehensive Heterocyclic ChemistryPergamon Press) from analogous precursors.

Further reaction of the compounds prepared according to 1. or 4., withsubsequent elimination of any protective groups,

H—B—Ar  (III)

to give compounds of the formula V takes place by linkage to compoundsof the formula XVI

Q—A—Q′  (XVI),

where Q and Q′ are leaving groups, under conditions known per se.

The substances of the formulae II, IV, VI and of the formulae P—Ar,NH₂—Ar, W—B¹ and W—B²—P¹, which are required as starting materials forsynthesizing the novel compounds, are known or can be synthesized fromanalogous precursors by processes described in the literature (e.g. B.Schulze, K. Illgen J. prakt. Chem. 1997, 339, 1 or K. Auer, E.Hungerbühler, R. W. Lang Chimia 1990, 44, 120 or A. Yokoo et al. Bull.Chem. Soc. Jpn. 1956, 29, 631 or L. Börjeson et al. Acta Chem. Chem.[sic] 1991, 45, 621 or Organikum Barth Dt. Verl. der Wiss. 1993 or A. R.Katritzky, C. W. Rees (ed.) Comprehensive Heterocyclic ChemistryPergamon Press or The Chemistry of Heterocyclic Compounds J. Wiley &Sons Inc. New York and the literature cited in each of these).

The reactions described above generally take place in an inert organicsolvent, e.g. dimethylformamide, acetonitrile, dichloromethane, dimethylsulfoxide, dimethoxyethane, toluene, ethyl acetate, xylene, a ketonesuch as acetone or methyl ethyl ketone, an alcohol such as ethanol orn-butanol, or a cyclic saturated ether, e.g. tetrahydrofuran or dioxane.

The reactions generally take place at from 20° C. to the boiling pointof the solvent and are generally complete within 1 to 20 hours. Anacid-binding agent is present if required, such as sodium or potassiumcarbonate, sodium methoxide, sodium ethoxide, sodium hydride,organometallic compounds (butyllithium, alkylmagnesium compounds),potassium t-butoxide, pyridine or triethylamine.

The reactions take place where appropriate with use of a catalyst suchas transition metals and complexes thereof, e.g. Pd—C, Pd(PPh₃)₄,Pd(OAc)₂, Pd(P(oTol)₃)₄, Pd₂(dba)₃ or Ni(COD)₂.

The crude product is isolated in a conventional way, for example byfiltration, removal of the solvent by distillation or extraction fromthe reaction mixture.

The novel compounds of the formula I can be purified either byrecrystallization from conventional organic solvents or by columnchromatography.

The invention includes not only the free 2-substituted1,2-benzoisothiazole derivatives but also the addition salts ofcompounds of the formula I with physiologically tolerated acids.Examples of suitable physiologically tolerated organic and inorganicacids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaricacid, adipic acid or benzoic acid. Further acids which can be used aredescribed in “Forschritte der Arzneimittelforschung”, Volume 10, pages224 et seq., Birkhäuser Verlag, Basel and Stuttgart, 1966.

The acid addition salts are prepared in a conventional way by mixing thefree base with the appropriate acid, where appropriate in solution in anorganic solvent, for example a lower alcohol such as methanol, ethanolor propanol, an ether such as methyl t-butyl ether, a ketone such asacetone or methyl ethyl ketone or an ester such as ethyl acetate.

The invention accordingly also relates to a therapeutic compositionwhich comprises a compound of the formula I or its pharmacologicallyacceptable acid addition salt as active ingredient in addition toconventional excipients and diluents, and to the use of the novelcompounds for controlling diseases.

The novel compounds can be administered in a conventional way orally orparenterally, intravenously or intramuscularly. The dosage depends onthe age, condition and weight of the patient and on the mode ofadministration. As a rule, the daily dose of active ingredient is about1-100 mg/kg of body weight on oral administration and 0.1-10 mg/kg ofbody weight on parenteral administration.

The novel compounds can be used in conventional solid or liquidpharmaceutical forms, e.g. as uncoated or (film-)coated tablets,capsules, powders, granules, suppositories, solutions, ointments, creamsor sprays. These are produced in a conventional way. The activeingredients can for this purpose be processed with conventionalpharmaceutical auxiliaries such as tablet binders, bulking agents,preservatives, tablet disintegrants, flow regulators, plasticizers,wetting agents, dispersants, emulsifiers, solvents, release-slowingagents, antioxidants and/or propellant gases (cf. H. Sucker et al.:Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). Theadministraton forms obtained in this way normally contain from 1 to 99%by weight of active ingredient.

The novel compounds have a high affinity for the 5HT_(1B), 5-HT_(1D) and5-HT_(1A) serotonin receptors. The affinity for these receptors ismoreover approximately the same, at least of the same order ofmagnitude. Furthermore, some of the novel compounds show good serotoninreuptake inhibition, which is a principle implemented in mostantidepressants.

These compounds are suitable as drugs for treating pathological statesin which the serotonin concentration is reduced and in which it iswished as part of a treatment to block specifically the activity of the5-HT_(1B), 5-HT_(1A) and 5-HT_(1D) presynaptic receptors without greatlyaffecting the other receptors at the same time. An example of apathological state of this type is depression.

The compounds of the present invention may also be beneficial fortreating mood disturbances with a central nervous causation, such asseasonal affective disorder and dysthymia. These also include anxietystates such as generalized anxiety, panic attacks, sociophobia,obsessive-compulsive neuroses and post-traumatic stress symptoms, memorydisturbances including dementia, amnesias and age-related memory loss,and psychogenic eating disorders such as anorexia nervosa and bulimianervosa.

The novel compounds may additionally be beneficial for treatingendocrine disorders such as hyperprolactinemia and for treatingvasospasms (especially of the cerebral vessels), hypertension andgastrointestinal disorders associated with motility and secretiondisturbances. Another area of use comprises sexual disorders.

The following examples serve to illustrate the invention withoutrestricting it.

EXAMPLE 1

3,3-Dimethyl-2-[3-(4-(5-tetralinyl)-1-piperazinyl)prop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide

Preparation of the Starting Materials

a) 3,3-Dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide

This compound was prepared in a manner known from the literature (K.Auer, E. Hungerbühler, R. W. Lang Chimia 1990, 44, 120).3,3-Diethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide (melting point174° C.) and 3,3-dimethyl-6-nitro-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 187° C.) were obtained in a similar way.

b) 2-(3-Chloroprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benzoisothia-zole1,1-dioxide

A solution of 5.9 g (3 mmol) of3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide in 150 ml ofDMF at room temperature was, after addition of 3.7 g (3.3 mmol) ofpotassium t-butoxide, heated under nitrogen to 80° C. Then 14.2 g (9mmol) of 1-bromo-3-chloropropane were rapidly added and the mixture wasstirred at 100° C. for 30 min. Pouring into ice-water was followed byextraction with ether, and the organic phases were washed with water,dried with sodium sulfate and then evaporated so that the productresulted as crystals which could be filtered off with suction. 6.7 g(82%) of substance were obtained. Melting point 107° C.

2-(3-Chloroprop-1-yl)-3,3-diethyl-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 70° C.),2-(3-chloroprop-1-yl)-3,3-dimethyl-6-nitro-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 146° C.),2-(2-chloroethyl)-3,3-diethyl-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (oil),2-(2-chloroethyl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (oil),2-(3-chloro-2-methyleneprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 115° C.) and2-(3-chloropropyl)-3,3-dimethyl-6-nitro-2,3-dihydro-1,2-benzoiso-thiazole1,1-dioxide (melting point 146° C.) were obtained in a similar way.

c) 1-(5-Tetralinyl)piperazine

14.7 g (0.1 mol) of 5-aminotetralin were refluxed with 18 g (0.11 mol)of bis(β-chloroethyl)amine hydrochloride in 300 ml of n-butanol for 48 hand, after cooling, 5.4 g of sodium carbonate were added and the mixturewas refluxed for a further 20 h. The precipitate which formed on coolingwas filtered off with suction and taken up in water, and 2N sodiumhydroxide solution was added. The aqueous phase was extracted with ethylacetate, and washing with water and drying over sodium sulfate werefollowed by evaporation under reduced pressure. It was possible in thisway to isolate 10.7 g (50%) of the product as an oil.

4-(1-Piperazinyl)isoquinoline

4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butylpiperazine-N-carboxylate, 0.1 g (0.11 mmol) oftris-(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 2.92 g (30.4 mmol) ofsodium t-butoxide were mixed in 50 ml of toluene and stirred at 75° C.for 2 h. The reaction mixture was added to ice/sodium chloride andextracted with ethyl acetate, the organic phase was dried over sodiumsulfate, and the solvent was removed in a rotary evaporator. The productcrystallized out and was filtered off with suction and washed withpentane. 5.5 g (81%) of the Boc-protected piperazine were obtained(melting point 111° C.). 5.2 g (16.6 mmol) of this substance were takenup in 17 ml of dichloromethane and, at 0° C., 17 ml (0.22 mol) oftrifluoroacetic acid were slowly added. The mixture was stirred at 0° C.for 4 h, poured into ice-water and extracted with dichloromethane. Theaqueous phase was filtered, made alkaline and extracted withdichloromethane. Drying over sodium sulfate and substantial removal ofthe solvent were followed by dilution with diethyl ether andprecipitation of the hydrochloride with ethereal hydrochloric acid. 3.2g (67%) of the product were obtained. (Melting point 293° C.).

The following compounds were prepared by processes similar to the twodescribed: 1-(1-naphthyl)diazepane (85° C., hydrochloride),1-(1-naphthylmethyl)piperazine (oil), 4-(1-piperazinyl)indan (oil),1-(1-naphthyl)piperazine (82° C.),4-chloro-1-(1-piperazinyl)-phthalazine (205° C., decomposition) and4-(1-piperazinyl)-quinazoline (320° C., hydrochloride). Otherderivatives were commercially available.

Preparation of the Final Product

1.1 g (5.2 mmol) of 1-(5-tetralinyl)piperazine, 1.5 ml of triethylamineand a trace of potassium iodide were added to a solution of 1.64 g (6.0mmol) of2-(3-chloroprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide in 40 ml of DMF. The reaction mixture was stirred at 100° C.for four hours and then poured in ice-water, and the resultingprecipitate was filtered off with suction. Purification took place byrecrystallization from isopropanol to result in 1 g (43%) of the product(melting point 140° C.).

NMR: CDCl₃ δ7.8 (d, 1H), 7.6 (dd, 1H), 7.5 (dd, 1H), 7.4 (d, 1H), 7.1(dd, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 3.4 (t, 2H), 3.0-2.5 (m, 14H), 2.1(tt, 2H), 1.8-1.7 (m, 4H), 1.5 (s, 6H) ppm.

The following compounds were obtained in a similar way:

EXAMPLE 2

3,3-Dimethyl-2-[3-(4-(2-phenyl-4-quinazolinyl)-1-piperazinyl)prop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 269° C., hydrochloride).

EXAMPLE 3

3,3-Dimethyl-2-[3-(4-(2-quinolinyl)-1-piperazinyl)-prop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 63° C.).

EXAMPLE 4

3,3-Dimethyl-2-[3-(4-(1-naphthyl)-1-diazepanyl)-prop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 126° C., hydrochloride).

EXAMPLE 5

3,3-Dimethyl-2-[3-(4-(4-chloro-1-phthalazinyl)-1-piperazinyl)-eth-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 190° C.).

EXAMPLE 6

3,3-Dimethyl-2-[3-(4-(1-naphthyl)-1-piperazinyl)-2-methyleneprop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 193° C.).

EXAMPLE 7

3,3-Dimethyl-2-[2-(4-(4-quinazolinyl)-1-piperazinyl)-eth-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 178° C., hydrochloride).

EXAMPLE 8

3,3-Dimethyl-2-[2-(4-(1-naphthyl)-1-piperazinyl)-eth-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 282° C., hydrochloride).

EXAMPLE 9

3,3-Dimethyl-2-[2-(4-isoquinolin-4-yl)-1-piperazinyl)-eth-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 243° C., hydrochloride).

EXAMPLE 10

3,3-Diethyl-2-[2-(4-(1-naphthyl)-1-piperazinyl)-eth-1-yl]-2,3-di-hydro-1,2-benzoisothiazole1,1-dioxide (oil).

EXAMPLE 11

3,3-Dimethyl-2-[3-(4-(1-naphthyl)-1-piperazinyl)-prop-1-yl]-6-(1-pyrrolyl)-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 269° C., hydrochloride).

The pyrrole ring was assembled by reacting3,3-dimethyl-2-[3-(4-(1-naphthyl)-1-piperazinyl)prop-1-yl]-6-amino-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide with 2,5-dimethoxytetrahydrofuran in glacial acetic acid at100° C. (1 h) in 86% yield.

EXAMPLE 12

3,3-Dimethyl-2-[3-(4-(1-naphthyl)-1-piperazinyl)-prop-1-yl]-6-benzoylamido-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 127° C.).

EXAMPLE 13

3,3-Dimethyl-2-[3-(4-(1-naphthyl)-1-piperazinyl)-prop-1-yl]-6-nitro-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 203° C.).

EXAMPLE 14

3,3-Dimethyl-2-[2-(4-(2,3-dimethylphenyl)-1-piperazinyl)eth-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 291° C., hydrochloride).

EXAMPLE 15

3,3-Dimethyl-2-[2-(4-(4-indanyl)-1-piperazinyl)-eth-1-yl]-2,3-di-hydro-1,2-benzoisothiazole1,1-dioxide (melting point 271° C., hydrochloride).

EXAMPLE 16

3,3-Dimethyl-2-[3-(4-(4-chloro-1-naphthyl)-1-piperazinyl)prop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 151° C.).

EXAMPLE 17

3,3-Dimethyl-2-[3-(4-(2-pyrimidinyl)-1-piperazinyl)-prop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 263° C., hydrochloride).

EXAMPLE 18

3,3-Dimethyl-2-[2-(4-(4-methoxyphenyl)-1-piperazinyl)eth-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 207° C., hydrochloride).

EXAMPLE 19

3,3-Dimethyl-2-[3-(4-(2-methoxyphenyl)-1-piperazinyl)-2-hydroxy-prop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 160° C.).

EXAMPLE 20

3,3-Diethyl-2-[3-(4-(1-naphthyl)-1-piperazinyl)-prop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 179° C.).

EXAMPLE 21

3,3-Dimethyl-2-[3-(4-(2,5-dimethylphenyl)-1-piperazinyl)prop-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 218° C., hydrochloride).

EXAMPLE 22

3,3-Dimethyl-2-[2-(4-(2-cyanophenyl)-1-piperazinyl)eth-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide (melting point 228° C., hydrochloride).

EXAMPLE 23

3,3-Dimethyl-2-[2-(4-(1-naphthyl)-1-piperazinyl)-eth-1-yl]-4-chloro-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide.

Preparation of the Starting Materials

a) 4-Chloro-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide

This compound was prepared as in Example 1a). Yield 7.8 g (70%).(Melting point 121° C.)

b)2-(2,2-Diethoxyeth-1-yl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide

7.7 g (33 mmol) of4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide, 8.25ml (55 mmol) of bromoacetaldehyde diethyl acetal and 7.0 g of potassiumcarbonate were taken up in 100 ml of dry DMF and stirred at 120° C. for5 h. The reaction mixture was poured into ice-water and then extractedwith ethyl acetate, and the organic phase was washed with water anddried over sodium sulfate. The solvent was removed under reducedpressure, the crude product was purified by column chromatography. 7.5 g(65%) of the product were obtained as an oil in this way.

c)2-(2-Oxoeth-1-yl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide

7.5 g (21.5 mmol) of2-(2,2-diethoxyeth-1-yl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide and 25 ml of concentrated hydrochloric acid were taken up in25 ml of water and 150 ml of THF and stirred at 40° C. for 1.5 H [sic].The reaction mixture was neutralized with sodium hydroxide solution andextracted with ether, and the organic phase was dried over sodiumsulfate and concentrated under reduced pressure. 5.8 g (98%) of theproduct were isolated as oil in this way.

Preparation of the Final Product

1.5 g (5.5 mmol) of the aldehyde 24 c), 1.06 g (5 mmol) ofnaphthylpiperazine (pepared as in Example 1c)) and 0.42 g (7 mmol) ofglacial acetic acid in 50 ml of ethanol were stirred at room temperaturefor 30 min and then 0.5 g (8 mmol) of sodium cyanoborohydride was slowlyadded. The mixture was stirred at room temperature for 2 h and thenpoured into an ice/salt mixture and extracted with dichloromethane.Drying with sodium sulfate, removal of the solvent by distillation andsubsequent recrystallization from ethanol resulted in 0.9 g (39%) ofcolorless crystals (melting point 156° C.).

NMR:CDCl₃ δ=8.3 (m, 1H), 7.8 (m, 1H), 7.7 (d, 1H), 7.6-7.3 (m, 6H), 7.1(d, 1H), 3.5 (t, 2H), 3.2 (m, 4H), 3.0-2.8 (m, 6H), 1.8 (s, 6H) ppm.

EXAMPLE 24

Preparation of3,3-dimethyl-2-[2-(4-(1-naphthyl)tetrahydro-1,2,3,6-pyridin-1-yl)eth-1-yl]2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide

Synthesis of the Starting Materials

a) N-Boc-4-(Trifluoromethanesulfonyloxy)tetrahydro-1,2,3,6-pyridine

A solution of 13.2 g (0.13 mol) of diisopropylamine in 200 ml of THF wasdeprotonated at −78° C. with 100 ml nBuLi (1.6M in hexane) and, after 30minutes at this temperature, 20.0 g (0.1 mol) of N-Boc-piperidonedissolved in 50 ml of THF were added dropwise. After a further threehours at −78° C., a solution of 39.3 g (0.11 mol) ofN,N,-bistrifluoromethanesulfonylaniline in 50 ml of THF was added, andthe mixture was allowed to reach room temperature overnight. For workup,water was added, the mixture was extracted with ether, the organicphases were washed with NaHCO₃ solution and water and dried over sodiumsulfate, and the solvent was evaporated off. The crude product waspurified by flash chromatography (silica gel, mobile phase heptane/ethylacetate=3/1).

Yield: 20.2 g (60% of theory)

¹H-NMR:(270 MHz,CDCl3 [sic]) δ=1.4 (s, 9H); 2.4(m, 2H); 3.6 (t, 2H); 4.1(m, 2H); 5.8 (m, 1H) ppm.

b) N-Boc-4-(1-Naphthyl)tetrahydro-1,2,3,6-pyridine

22 ml of 2M sodium carbonate solution, 7.63 g (44.4 mmol) ofnaphthyl-1-boronic acid, 4.13 g (97.6 mmol) of lithium chloride, 0.85 g(4.44 mmol) of copper(I) iodide and 2.1 g (1.77 mmol) oftetrakistriphenylpalladium [sic] were successively added to 14.7 g (44.4mmol) of the compound described above, dissolved in 115 ml ofdimethoxyethane, and the mixture was boiled for 4 h. For workup, aqueousammonia solution was added and extractive workup was carried out withwater and ethyl acetate, and the residue obtained after drying oversodium sulfate and evaporation of the solvent was purified by flashchromatograpy (silica gel, mobile phase heptane/ethyl acetate=4/1).

Yield: 8.2 g (57% of theory)

¹H-NMR (270 MHz, CDCl3 [sic]): δ=1.4 (s, 9H); 2.5 (m, 2H); 3.7(t, 2H);4.1 (m, 2H); 5.8 (m, 1H); 7.2-7.5 (m, 3H); 7.3-8.0 (m, 3H) ppm.

c) 4-(1-Naphthyl)tetrahydro-1,2,3,6-pyridine

7.84 g (25.3 mmol) of N-Boc-4-(1-naphthyl)-3,6-dihydro-2H-pyridine werestirred with 200 ml of ethereal hydrochloric acid at room temperatureovernight, and the precipitated product was filtered off and dried.

Yield: 5.5 g (88% of theory).

d) Preparation of the Final Compound 1.0 g (4.1 mmol) of the compound24c described above was dissolved in 20 ml of methanol and, in thepresence of 2.22 g (16.8 mmol) of zinc(II) chloride, firstly 1.27 g (5.3mmol) of the aldehyde described in Example 23c and then 0.5 g (8.14mmol) of sodium cyanoborohydride were added. After 16 h at roomtemperature, workup was carried out as described, and the resultingcrude product was purified by chromatography (silica gel, mobile phasedichloromethane/methanol=97/3). A white solid was obtained byprecipitating the salt with ethereal hydrochloric acid solution.

Yield: 0.9 g (47% of theory)

¹H-NMR (270 MHz, DMSO-d6 [sic]): δ=1.6 (m, 6H);2.6 (m, 1H); 3.1 (m, 1H);3.4-3.6 (m, 6H); 4.0-4.2 (m, 2H); 5.8 (sbr, 1H); 7.6-8.0 (m, 7H); 8.2(d, 1H); 12.0 (s, 1H) ppm.

EXAMPLE 25

Preparation of3,3-dimethyl-2-[2-(4-(1-naphthyl)-1-piperidinyl)eth-1-yl]-2,3-dihydro-1,2-benzoisothiazole1,1-dioxide

a) 4-(1-Naphthyl)piperidine

3.7 g (15.3 mmol) of 4-(1-naphthyl)-1,2,3,6-tetrahydropyridine weredissolved in methanol and hydrogenated, with the addition of 0.8 g ofpalladium on carbon, with hydrogen at room temperature for 48 h. Thecatalyst was filtered off, and the solvent was evaporated off.

Yield: 1.8 g (56% of theory)

¹H-NMR (270 MHz, CDCl3 [sic]) δ=1.6-1.8 (m, 2H); 2.0 (m, 2H); 2.9 (dt,2H); 3.3 (d, 2H); 3.5 (tt, 1H); 7.4-7.6 (m, 4H); 7.7 (d, 1H); 7.9 (d,1H); 8.1 (d, 1H) ppm.

Preparation of the Final Compound

1.5 g (7.1 mmol) of the amine 25a were dissolved in 20 ml of methanoland firstly 3.8 g (28.4 mmol) of zinc chloride and 2.21 g (9.2 mmol) ofthe aldehyde described in Example 23c, dissolved in 15 ml of methanol,were added, and then 0.89 g (14.2 mmol) of sodium cyanoborohydride wasadded in portions. After stirring for six hours, insolubles werefiltered off, and the mother liquid was concentrated and taken up inethyl acetate. The organic phase was washed with water and saturatedbrine, dried over sodium sulfate, filtered and concentrated to afford ayellowish oil.

Yield: 2.2 g (65% of theory)

¹H-NMR (270 MHz, CDCl₃): δ=1.7-1.9 (m, 8H); 2.0 (m, 2H); 2.7-3.0 (m,4H); 3.2 (m, 2H); 3.5 (m, 1H); 3.7 (t, 2H); 7.1 (d, 1H); 7.3-7.7 (m,9H); 8.2 (d, 1H) ppm.

Further preferred novel compounds of the formula I are listed in thefollowing table.

I

No R¹/R² R³ R⁴ R⁵ R⁶ R⁷ A B Ar  26 Me H H / / / C₂ 4-Piperazine 2-Me—Ph 27 Me H H / / / C₂ 4-Piperazine 2-OH—Ph  28 Me H H / / / C₂4-Piperazine 2-Br—Ph  29 Me H H / / / C₂ 4-Piperazine 2-CF₃—Ph  30 Me HH / / / C₂ 4-Piperazine 2-OEt—Ph  31 Me H H Me Me / C₂ 4-Piperazine2-NR⁵R⁶—Ph  32 Me H H / / / C₂ 4-Piperazine 2-O(n-C₄)—Ph  33 Me H H / // C₂ 4-Piperazine 2-NO₂—Ph  34 Me H H / / / C₂ 4-Piperazine 2-F—Ph  35Me H H / / / C₂ 4-Piperazine 2-OMe—Ph  36 Me H H / / / C₂ 4-Piperazine2-CN—Ph  37 Me H H / / / C₂ 4-Piperazine 2-Cl—Ph  38 Me H H / / H C₂4-Piperazine 2-CO₂R⁷—Ph  39 Me H H / / Me C₂ 4-Piperazine 2-CO₂R⁷—Ph  40Me H H H H / C₂ 4-Piperazine 2-NR⁵R⁶—Ph  41 Me H H n-C₃ n-C₃ / C₂4-Piperazine 2-NR⁵R⁶—Ph  42 Me H H i-C₃ i-C₃ / C₂ 4-Piperazine2-NR⁵R⁶—Ph  43 Me H H / / / C₂ 4-Piperazine 2-I—Ph  44 Me H H / / i-C₃C₂ 4-Piperazine 2-CO₂R⁷—Ph  45 Me H H / / / C₂ 4-Piperazine Ph  46 Me HH / / / C₂ 4-Piperazine 2-Et—Ph  47 Me H H / / / C₂ 4-Piperazine2-iC₃—Ph  48 Me H H / / / C₂ 4-Piperazine 3-Ph—Ph  49 Me H H / / / C₂4-Piperazine 3-tBu—Ph  50 Me H H / / / C₂ 4-Piperazine 3-Et—Ph  51 Me HH / / Et C₂ 4-Piperazine 3-CO₂R⁷—Ph  52 Me H H / / / C₂ 4-Piperazine3-I—Ph  53 Me H H / / / C₂ 4-Piperazine 3-Cl—Ph  54 Me H H / / / C₂4-Piperazine 3-Br—Ph  55 Me H H / / / C₂ 4-Piperazine 3-F—Ph  56 Me H H/ / / C₂ 4-Piperazine 3-CF₃—Ph  57 Me H H / / / C₂ 4-Piperazine 3-OH—Ph 58 Me H H / / H C₂ 4-Piperazine 3-CO₂R⁷—Ph  59 Me H H H H / C₂4-Piperazine 3-NR⁵R⁶—Ph  60 Me H H Me Me / C₂ 4-Piperazine 3-NR⁵R⁶—Ph 61 Me H H i-C₃ i-C₃ / C₂ 4-Piperazine 3-NR⁵R⁶—Ph  62 Me H H / / / C₂4-Piperazine 3-CN—Ph  63 Me H H / / / C₂ 4-Piperazine 3-OMe—Ph  64 Me HH / / / C₂ 4-Piperazine 3-NO₂—Ph  65 Me H H / / / C₂ 4-Piperazine3-OEt—Ph  66 Me H H / / / C₂ 4-Piperazine 3-O(n-C₅)Ph  67 Me H H / / /C₂ 4-Piperazine 4-Ph—Ph  68 Me H H / / / C₂ 4-Piperazine 4-iC₃—Ph  69 MeH H / / / C₂ 4-Piperazine 4-nC₃—Ph  70 Me H H / / / C₂ 4-Piperazine4-nC₆—Ph  71 Me H H / / / C₂ 4-Piperazine 4-I—Ph  72 Me H H / / / C₂4-Piperazine 4-F—Ph  73 Me H H / / / C₂ 4-Piperazine 4-Br—Ph  74 Me H H/ / / C₂ 4-Piperazine 4-Cl—Ph  75 Me H H / / / C₂ 4-Piperazine 4-OH—Ph 76 Me H H / / / C₂ 4-Piperazine 4-CN—Ph  77 Me H H / / / C₂4-Piperazine 4-CF₃—Ph  78 Me H H / / / C₂ 4-Piperazine 4-NO₂—Ph  79 Me HH H H / C₂ 4-Piperazine 4-NR⁵R⁶—Ph  80 Me H H Me Me / C₂ 4-Piperazine4-NR⁵R⁶—Ph  81 Me H H n-C₄ n-C₄ / C₂ 4-Piperazine 4-NR⁵R⁶—Ph  82 Me H HMe Et / C₂ 4-Piperazine 4-NR⁵R⁶—Ph  83 Me H H / / H C₂ 4-Piperazine4-CO₂R⁷—Ph  84 Me H H / / Me C₂ 4-Piperazine 4-CO₂R⁷—Ph  85 Me H H / /n-C₅ C₂ 4-Piperazine 4-CO₂R⁷—Ph  86 Me H H / / / C₂ 4-Piperazine4-OMe—Ph  87 Me H H / / / C₂ 4-Piperazine 4-OEt—Ph  88 Me H H / / / C₂4-Piperazine 2-Cl,4-NO₂—Ph  89 Me H H / / / C₂ 4-Piperazine 3-Cl,4-Me—Ph 90 Me H H / / / C₂ 4-Piperazine 2-CN,6-CN—Ph  91 Me H H / / / C₂4-Piperazine 2-Me,6-Me—Ph  92 Me H H / / / C₂ 4-Piperazine2-NO₂,4-CF₃—Ph  93 Me H H / / / C₂ 4-Piperazine 3-Cl,4-Cl—Ph  94 Me H H/ / / C₂ 4-Piperazine 2-Me,3-Me—Ph  95 Me H H / / / C₂ 4-Piperazine2-Et,3-Et—Ph  96 Me H H H H / C₂ 4-Piperazine 2-NR⁵R⁶,4-Cl—Ph  97 Me H HH H / C₂ 4-Piperazine 2-NR⁵R⁶,4-Me—Ph  98 Me H H Me Me / C₂ 4-Piperazine2-NR⁵R⁶,4-Cl—Ph  99 Me H H / / / C₂ 4-Piperazine 3-Me,4-Me—Ph 100 Me H H/ / / C₂ 4-Piperazine 3-Cl,5-Cl—Ph 101 Me H H / / / C₂ 4-Piperazine2-OMe,4-OMe—Ph 102 Me H H / / / C₂ 4-Piperazine 3-tBu,5-tBu—Ph 103 Me HH / / / C₂ 4-Piperazine 3-tBu,5-CF₃—Ph 104 Me H H / / / C₂ 4-Piperazine2-OMe,5-Cl—Ph 105 Me H H / / / C₂ 4-Piperazine 2-OMe,5-OMe—Ph 106 Me H H/ / / C₂ 4-Piperazine 2-OMe,5-Ph—Ph 107 Me H H / / / C₂ 4-Piperazine2-OMe,4-OMe—Ph 108 Me H H / / / C₂ 4-Piperazine 3-CF₃,4-Cl—Ph 109 Me H H/ / / C₂ 4-Piperazine 2-NO₂,4-CF₃,5-NO₂—Ph 110 Me H H H H / C₂4-Piperazine 2-NR⁵R⁶,4-Me,5-Cl—Ph 111 Me H H / / / C₂ 4-Piperazine2-OMe,3-Cl,5-Cl—Ph 112 Me H H / / / C₂ 4-Piperazine 2-OMe,4-NO₂,5-Me—Ph113 Me H H / / / C₂ 4-Piperazine 2-OMe,4-Cl,5-Me—Ph 114 Me H H / / / C₂4-Piperazine 2-Me,4-Cl,5-CF₃—Ph 115 Me H H / / / C₂ 4-Piperazine5-Tetralin 116 Me H H / / / C₂ 4-Piperazine 4-Indan 117 Me H H / / / C₂4-Piperazine 1-Tetralin 118 Me H H / / / C₂ 4-Piperazine 1-Indan 119 MeH H / / / C₂ 4-Piperazine 1-Naphthalene 120 Me H H / / / C₂ 4-Piperazine2-OMe-1-Naphthalene 121 Me H H / / / C₂ 4-Piperazine 2-OEt-1-Naphthalene122 Me H H / / / C₂ 4-Piperazine 2-Me-1-Naphthalene 123 Me H H / / / C₂4-Piperazine 2-Et-1-Naphthalene 124 Me H H / / / C₂ 4-Piperazine8-OMe-1-Naphthalene 125 Me H H / / / C₂ 4-Piperazine 8-Me-1-Naphthalene126 Me H H / / / C₂ 4-Piperazine 9-Anthracene 127 Me H H / / / C₂4-Piperazine 3-Indole 128 Me H H / / / C₂ 4-Piperazine 2-Quinazoline 129Me H H / / / C₂ 4-Piperazine 4-Quinazoline 130 Me H H / / / C₂4-Piperazine 2-Quinoxaline 131 Me H H / / / C₂ 4-Piperazine1-Phthalazine 132 Me H H / / / C₂ 4-Piperazine 2-Quinoline 133 Me H H // / C₂ 4-Piperazine 3-Quinoline 134 Me H H / / / C₂ 4-Piperazine4-Quinoline 135 Me H H / / / C₂ 4-Piperazine 5-Quinoline 136 Me H H / // C₂ 4-Piperazine 1-Isoquinoline 137 Me H H / / / C₂ 4-Piperazine4-Isoquinoline 138 Me H H / / / C₂ 4-Piperazine 8-Isoquinoline 139 Me HH / / / C₂ 4-Piperazine 7-Benzofuran 140 Me H H / / / C₂ 4-Piperazine3-2H-Chromene 141 Me H H / / / C₂ 4-Piperazine 5-Chroman 142 Me H H / // C₂ 4-Piperazine 8-Chroman 143 Me H H / / / C₂ 4-Piperazine2-Pyrimidine 144 Me H H / / / C₂ 4-Piperazine 2-tBu,4-CF₃-6-Pyrimidine145 Me H H / / / C₂ 4-Piperazine 5-OMe-4-Pyrimidine 146 Me H H / / / C₂4-Piperazine 4-Pyrimidine 147 Me H H / / / C₂ 4-Piperazine 2-Pyrazine148 Me H H / / / C₂ 4-Piperazine 3-Isoxazole 149 Me H H / / / C₂4-Piperazine 2-Pyridine 150 Me H H / / / C₂ 4-Piperazine 3-Pyridine 151Me H H / / / C₂ 4-Piperazine 3-Pyrrole 152 Me H H / / / C₂ 4-Piperazine2-Ph-4-Quinazoline 153 Me H H / / / C₂ 4-Piperazine 6-iC₃-4-Pyrimidine154 Me H H / / / C₂ 4-Piperazine 7-OMe-1-Naphthalene 155 Me H H / / / C₂4-Piperidine 2-Me—Ph 156 Me H H / / / C₂ 4-Piperidine 2-OH—Ph 157 Me H H/ / / C₂ 4-Piperidine 2-Br—Ph 158 Me H H / / / C₂ 4-Piperidine 2-CF₃—Ph159 Me H H / / / C₂ 4-Piperidine 2-OEt—Ph 160 Me H H Me Me / C₂4-Piperidine 2-NR⁵R⁶—Ph 161 Me H H / / / C₂ 4-Piperidine 2-O(n-C₄)—Ph162 Me H H / / / C₂ 4-Piperidine 2-NO₂—Ph 163 Me H H / / / C₂4-Piperidine 2-F—Ph 164 Me H H / / / C₂ 4-Piperidine 2-OMe—Ph 165 Me H H/ / / C₂ 4-Piperidine 2-CN—Ph 166 Me H H / / / C₂ 4-Piperidine 2-Cl—Ph167 Me H H / / H C₂ 4-Piperidine 2-CO₂R⁷—Ph 168 Me H H / / Me C₂4-Piperidine 2-CO₂R⁷—Ph 169 Me H H H H / C₂ 4-Piperidine 2-NR⁵R⁶—Ph 170Me H H n-C₃ n-C₃ / C₂ 4-Piperidine 2-NR⁵R⁶—Ph 171 Me H H i-C₃ i-C₃ / C₂4-Piperidine 2-NR⁵R⁶—Ph 172 Me H H / / / C₂ 4-Piperidine 2-I—Ph 173 Me HH / / i-C₃ C₂ 4-Piperidine 2-CO₂R⁷—Ph 174 Me H H / / / C₂ 4-PiperidinePh 175 Me H H / / / C₂ 4-Piperidine 2-Et—Ph 176 Me H H / / / C₂4-Piperidine 2-iC₃—Ph 177 Me H H / / / C₂ 4-Piperidine 3-Ph—Ph 178 Me HH / / / C₂ 4-Piperidine 3-tBu—Ph 179 Me H H / / / C₂ 4-Piperidine3-Et—Ph 180 Me H H / / Et C₂ 4-Piperidine 3-CO₂R⁷—Ph 181 Me H H / / / C₂4-Piperidine 3-I—Ph 182 Me H H / / / C₂ 4-Piperidine 3-Cl—Ph 183 Me H H/ / / C₂ 4-Piperidine 3-Br—Ph 184 Me H H / / / C₂ 4-Piperidine 3-F—Ph185 Me H H / / / C₂ 4-Piperidine 3-CF₃—Ph 186 Me H H / / / C₂4-Piperidine 3-OH—Ph 187 Me H H / / H C₂ 4-Piperidine 3-CO₂R⁷—Ph 188 MeH H H H / C₂ 4-Piperidine 3-NR⁵R⁶—Ph 189 Me H H Me Me / C₂ 4-Piperidine3-NR⁵R⁶—Ph 190 Me H H i-C₃ i-C₃ / C₂ 4-Piperidine 3-NR⁵R⁶—Ph 191 Me H H/ / / C₂ 4-Piperidine 3-CN—Ph 192 Me H H / / / C₂ 4-Piperidine 3-OMe—Ph193 Me H H / / / C₂ 4-Piperidine 3-NO₂—Ph 194 Me H H / / / C₂4-Piperidine 3-OEt—Ph 195 Me H H / / / C₂ 4-Piperidine 3-O(n-C₅)Ph 196Me H H / / / C₂ 4-Piperidine 4-Ph—Ph 197 Me H H / / / C₂ 4-Piperidine4-iC₃—Ph 198 Me H H / / / C₂ 4-Piperidine 4-nC₃—Ph 199 Me H H / / / C₂4-Piperidine 4-nC₆—Ph 200 Me H H / / / C₂ 4-Piperidine 4-I—Ph 201 Me H H/ / / C₂ 4-Piperidine 4-F—Ph 202 Me H H / / / C₂ 4-Piperidine 4-Br—Ph203 Me H H / / / C₂ 4-Piperidine 4-Cl—Ph 204 Me H H / / / C₂4-Piperidine 4-OH—Ph 205 Me H H / / / C₂ 4-Piperidine 4-CN—Ph 206 Me H H/ / / C₂ 4-Piperidine 4-CF₃—Ph 207 Me H H / / / C₂ 4-Piperidine 4-NO₂—Ph208 Me H H / / / C₂ 4-Piperidine 4-NR⁵R⁶—Ph 209 Me H H Me Me / C₂4-Piperidine 4-NR⁵R⁶—Ph 210 Me H H n-C₄ n-C₄ / C₂ 4-Piperidine4-NR⁵R⁶—Ph 211 Me H H Me Et / C₂ 4-Piperidine 4-NR⁵R⁶—Ph 212 Me H H / /H C₂ 4-Piperidine 4-CO₂R⁷—Ph 213 Me H H / / Me C₂ 4-Piperidine4-CO₂R⁷—Ph 214 Me H H / / n-C₅ C₂ 4-Piperidine 4-CO₂R⁷—Ph 215 Me H H / // C₂ 4-Piperidine 4-OMe—Ph 216 Me H H / / / C₂ 4-Piperidine 4-OEt—Ph 217Me H H / / / C₂ 4-Piperidine 2-Cl,4-NO₂—Ph 218 Me H H / / / C₂4-Piperidine 3-Cl,4-Me—Ph 219 Me H H / / / C₂ 4-Piperidine 2-CN,6-CN—Ph220 Me H H / / / C₂ 4-Piperidine 2-Me,6-Me—Ph 221 Me H H / / / C₂4-Piperidine 2-NO₂,4-CF₃—Ph 222 Me H H / / / C₂ 4-Piperidine3-Cl,4-Cl—Ph 223 Me H H / / / C₂ 4-Piperidine 2-Me,3-Me—Ph 224 Me H H // / C₂ 4-Piperidine 2-Et,3-Et—Ph 225 Me H H H H / C₂ 4-Piperidine2-NR⁵R⁶,4-Cl—Ph 226 Me H H H H / C₂ 4-Piperidine 2-NR⁵R⁶,4-Cl—Ph 227 MeH H Me Me / C₂ 4-Piperidine 2-NR⁵R⁶,4-Cl—Ph 228 Me H H / / / C₂4-Piperidine 3-Me,4,Me—Ph 229 Me H H / / / C₂ 4-Piperidine 3-Cl,5-Cl—Ph230 Me H H / / / C₂ 4-Piperidine 2-OMe,4-OMe—Ph 231 Me H H / / / C₂4-Piperidine 3-tBu,5-tBu—Ph 232 Me H H / / / C₂ 4-Piperidine3-tBu,5-CF₃—Ph 233 Me H H / / / C₂ 4-Piperidine 2-OMe,5-Cl—Ph 234 Me H H/ / / C₂ 4-Piperidine 2-OMe,5-OMe—Ph 235 Me H H / / / C₂ 4-Piperidine2-OMe,5-Ph—Ph 236 Me H H / / / C₂ 4-Piperidine 3-OMe,4-OMe—Ph 237 Me H H/ / / C₂ 4-Piperidine 3-CF₃,4-Cl—Ph 238 Me H H / / / C₂ 4-Piperidine2-NO₂,4-CF₃,5-NO₂—Ph 239 Me H H H H / C₂ 4-Piperidine2-NR⁵R⁶,4-Me,5-Cl—Ph 240 Me H H / / / C₂ 4-Piperidine 2-OMe,3-Cl,5-Cl—Ph241 Me H H / / / C₂ 4-Piperidine 2-OMe,4-NO₂,5-Me—Ph 242 Me H H / / / C₂4-Piperidine 2-OMe,4-Cl,5-Me—Ph 243 Me H H / / / C₂ 4-Piperidine2-Me,4-Cl,5-CF₃—Ph 244 Me H H / / / C₂ 4-Piperidine 5-Tetralin 245 Me HH / / / C₂ 4-Piperidine 4-Indan 246 Me H H / / / C₂ 4-Piperidine1-Tetralin 247 Me H H / / / C₂ 4-Piperidine 1-Indan 248 Me H H / / / C₂4-Piperidine 1-Naphthalene 249 Me H H / / / C₂ 4-Piperidine2-OMe-1-Naphthalene 250 Me H H / / / C₂ 4-Piperidine 2-OEt-1-Naphthalene251 Me H H / / / C₂ 4-Piperidine 2-Me-1-Naphthalene 252 Me H H / / / C₂4-Piperidine 2-Et-1-Naphthalene 253 Me H H / / / C₂ 4-Piperidine8-OMe-1-Naphthalene 254 Me H H / / / C₂ 4-Piperidine 8-Me-1-Naphthalene255 Me H H / / / C₂ 4-Piperidine 9-Anthracene 256 Me H H / / / C₂4-Piperidine 3-Indole 257 Me H H / / / C₂ 4-Piperidine 2-Quinazoline 258Me H H / / / C₂ 4-Piperidine 4-Quinazoline 259 Me H H / / / C₂4-Piperidine 2-Quinoxaline 260 Me H H / / ( C₂ 4-Piperidine1-Phthalazine 261 Me H H / / / C₂ 4-Piperidine 2-Quinoline 262 Me H H // / C₂ 4-Piperidine 3-Quinoline 263 Me H H / / / C₂ 4-Piperidine4-Quinoline 264 Me H H / / / C₂ 4-Piperidine 5-Quinoline 265 Me H H / // C₂ 4-Piperidine 1-Isoquinoline 266 Me H H / / / C₂ 4-Piperidine4-Isoquinoline 267 Me H H / / / C₂ 4-Piperidine 8-Isoquinoline 268 Me HH / / / C₂ 4-Piperidine 7-Benzofuran 269 Me H H / / / C₂ 4-Piperidine3-2H-Chromene 270 Me H H / / / C₂ 4-Piperidine 5-Chroman 271 Me H H / // C₂ 4-Piperidine 8-Chroman 272 Me H H / / / C₂ 4-Piperidine2-Pyrimidine 273 Me H H / / / C₂ 4-Piperidine 2-tBu,4-CF₃-6-Pyrimidine274 Me H H / / / C₂ 4-Piperidine 5-OMe-4-Pyrimidine 275 Me H H / / / C₂4-Piperidine 4-Pyrimidine 276 Me H H / / / C₂ 4-Piperidine 2-Pyrazine277 Me H H / / / C₂ 4-Piperidine 3-Isoxazole 278 Me H H / / / C₂4-Piperidine 2-Pyridine 279 Me H H / / / C₂ 4-Piperidine 3-Pyridine 280Me H H / / / C₂ 4-Piperidine 3-Pyrrole 281 Me H H / / / C₂ 4-Piperidine2-Ph-4-Quinazoline 282 Me H H / / / C₂ 4-Piperidine 6-iC₃-4-Pyrimidine283 Me H H / / / C₂ 4-Piperidine 7-OMe-1-Naphthalene 284 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Me—Ph 285 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OH—Ph 286 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Br—Ph 287 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-CF₃—Ph 288 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OEt—Ph 289 Me H H Me Me / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NR⁵R⁶—Ph 290 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-O(n-C₄)—Ph 291 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NO₂—Ph 292 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-F—Ph 293 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OMe—Ph 294 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-CN—Ph 295 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Cl—Ph 296 Me H H / / H C₂4-Tetrahydro-1,2,3,6-pyridine 2-CO₂R⁷—Ph 297 Me H H / / Me C₂4-Tetrahydro-1,2,3,6-pyridine 2-CO₂R⁷—Ph 298 Me H H H H / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NR⁵R⁶—Ph 299 Me H H n-C₃ n-C₃ / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NR⁵R⁶—Ph 300 Me H H i-C₃ i-C₃ / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NR⁵R⁶—Ph 301 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-I—Ph 302 Me H H / / i-C₃ C₂4-Tetrahydro-1,2,3,6-pyridine 2-CO₂R⁷—Ph 303 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine Ph 304 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Et—Ph 305 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-iC₃—Ph 306 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Ph—Ph 307 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-tBu—Ph 308 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Et—Ph 309 Me H H / / Et C₂4-Tetrahydro-1,2,3,6-pyridine 3-CO₂R⁷—Ph 310 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-I—Ph 311 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Cl—Ph 312 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Br—Ph 313 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-F—Ph 314 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-CF₃—Ph 315 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-OH—Ph 316 Me H H / / H C₂4-Tetrahydro-1,2,3,6-pyridine 3-CO₂R⁷—Ph 317 Me H H H H / C₂4-Tetrahydro-1,2,3,6-pyridine 3-NR⁵R⁶—Ph 318 Me H H Me Me / C₂4-Tetrahydro-1,2,3,6-pyridine 3-NR⁵R⁶—Ph 319 Me H H i-C₃ i-C₃ / C₂4-Tetrahydro-1,2,3,6-pyridine 3-NR⁵R⁶—Ph 320 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-CN—Ph 321 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-OMe—Ph 322 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-NO₂—Ph 323 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-OEt—Ph 324 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-O(n-C₅)Ph 325 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-Ph—Ph 326 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-iC₃—Ph 327 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-nC₃—Ph 328 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-nC₆—Ph 329 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-I—Ph 330 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-F—Ph 331 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-Br—Ph 332 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-Cl—Ph 333 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-OH—Ph 334 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-CN—Ph 335 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-CF₃—Ph 336 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-NO₂—Ph 337 Me H H H H / C₂4-Tetrahydro-1,2,3,6-pyridine 4-NR⁵R⁶—Ph 338 Me H H Me Me / C₂4-Tetrahydro-1,2,3,6-pyridine 4-NR⁵R⁶—Ph 339 Me H H n-C₄ n-C₄ / C₂4-Tetrahydro-1,2,3,6-pyridine 4-NR⁵R⁶—Ph 340 Me H H Me Me / C₂4-Tetrahydro-1,2,3,6-pyridine 4-NR⁵R⁶—Ph 341 Me H H / / H C₂4-Tetrahydro-1,2,3,6-pyridine 4-CO₂R⁷—Ph 342 Me H H / / Me C₂4-Tetrahydro-1,2,3,6-pyridine 4-CO₂R⁷—Ph 343 Me H H / / n-C₅ C₂4-Tetrahydro-1,2,3,6-pyridine 4-CO₂R⁷—Ph 344 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-OMe—Ph 345 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-OEt—Ph 346 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Cl,2,3,6-NO₂—Ph 347 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Cl,2,3,6-Me—Ph 348 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-CN,6-CN—Ph 349 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Me,6-Me—Ph 350 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NO₂,2,3,6-CF₃—Ph 351 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Cl,2,3,6-Cl—Ph 352 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Me,3-Me—Ph 353 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Et,3-Et—Ph 354 Me H H H H / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NR⁵R⁶,2,3,6-Cl—Ph 355 Me H H H H / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NR⁵R⁶,2,3,6-Me—Ph 356 Me H H Me Me / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NR⁵R⁶,2,3,6-Cl—Ph 357 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Me,2,3,6-Me—Ph 358 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Cl,5-Cl—Ph 359 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OMe,2,3,6-OMe—Ph 360 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-tBu,5-tBu—Ph 361 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-tBu,5-CF₃—Ph 362 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OMe,5-Cl—Ph 363 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OMe,5-OMe—Ph 364 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OMe,5-Ph—Ph 365 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OMe,2,3,6-OMe—Ph 366 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-CF₃,2,3,6-Cl—Ph 367 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-NO₂,2,3,6-CF₃, 5-NO₂—Ph 368 Me H H H H /C₂ 4-Tetrahydro-1,2,3,6-pyridine 2-NR⁵R⁶,2,3,6-Me, 5-Cl—Ph 369 Me H H // / C₂ 4-Tetrahydro-1,2,3,6-pyridine 2-OMe,3-Cl,5-Cl—Ph 370 Me H H / / /C₂ 4-Tetrahydro-1,2,3,6-pyridine 2-OMe,2,3,6-NO₂, 5-Me—Ph 371 Me H H / // C₂ 4-Tetrahydro-1,2,3,6-pyridine 2-OMe,2,3,6-Cl,5-Me—Ph 372 Me H H / // C₂ 4-Tetrahydro-1,2,3,6-pyridine 2-Me,2,3,6-Cl,5-CF₃—Ph 373 Me H H / // C₂ 4-Tetrahydro-1,2,3,6-pyridine 4-Tetraline 374 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-Indan 375 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 1-Tetralin 376 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 1-Indan 377 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 1-Naphthalene 378 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OMe-1-Naphthalene 379 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-OEt-1-Naphthalene 380 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Me-1-Naphthalene 381 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Et-1-Naphthalene 382 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 8-OMe-1-Naphthalene 383 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 8-Me-1-Naphthalene 384 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 9-Anthracene 385 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Indole 386 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Quinazoline 387 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-Quinazoline 388 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Quinoxaline 389 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 1-Phthalazine 390 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Quinoline 391 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Quinoline 392 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-Quinoline 393 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 5-Quinoline 394 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 1-Isoquinoline 395 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 4-Isoquinoline 396 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 8-Isoquinoline 397 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 7-Benzoferan [sic] 398 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-2H-Chromene 399 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 5-Chroman 400 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 8-Chroman 401 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Pyrimidine 402 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-tBu,2,3,6-CF₃-6- Pyrimidine 403 Me H H // / C₂ 4-Tetrahydro-1,2,3,6-pyridine 5-OMe-4-Pyrimidine 404 Me H H / / /C₂ 4-Tetrahydro-1,2,3,6-pyridine 4-Pyrimidine 405 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Pyrazine 406 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Isoxazole 407 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Pyridine 408 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Pyridine 409 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 3-Pyrrole 410 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 2-Ph-4-Quinazoline 411 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 6-iC₃-4-Pyrimidine 412 Me H H / / / C₂4-Tetrahydro-1,2,3,6-pyridine 7-OMe-1-Naphthalene 413 Me H H / / / C₂4-Homopiperazine 2-Me—Ph 414 Me H H / / / C₂ 4-Homopiperazine 2-OH—Ph415 Me H H / / / C₂ 4-Homopiperazine 2-Br—Ph 416 Me H H / / / C₂4-Homopiperazine 2-CF₃—Ph 417 Me H H / / / C₂ 4-Homopiperazine 2-OMe—Ph418 Me H H / / / C₂ 4-Homopiperazine 2-CN—Ph 419 Me H H / / / C₂4-Homopiperazine Ph 420 Me H H H H / C₂ 4-Homopiperazine 2-NR⁵R⁶—Ph 421Me H H Me Me / C₂ 4-Homopiperazine 2-NR⁵R⁶—Ph 422 Me H H / / H C₂4-Homopiperazine 2-CO₂R⁷—Ph 423 Me H H / / Me C₂ 4-Homopiperazine2-CO₂R⁷—Ph 424 Me H H / / / C₂ 4-Homopiperazine 3-tBu—Ph 425 Me H H / // C₂ 4-Homopiperazine 3-Me—Ph 426 Me H H / / / C₂ 4-Homopiperazine3-CF₃—Ph 427 Me H H / / / C₂ 4-Homopiperazine 3-Cl—Ph 428 Me H H / / /C₂ 4-Homopiperazine 3-OMe—Ph 429 Me H H / / / C₂ 4-Homopiperazine4-NO₂—Ph 430 Me H H / / / C₂ 4-Homopiperazine 4-Ph—Ph 431 Me H H / / /C₂ 4-Homopiperazine 4-F—Ph 432 Me H H / / / C₂ 4-Homopiperazine3-Cl,4-Me Ph 433 Me H H / / / C₂ 4-Homopiperazine 2-Me,6-Me Ph 434 Me HH / / / C₂ 4-Homopiperazine 2-Me,3-Me Ph 435 Me H H / / / C₂4-Homopiperazine 2-Et,3,-Et Ph 436 Me H H / / / C₂ 4-Homopiperazine3t-Bu,5-CF₃ Ph 437 Me H H / / / C₂ 4-Homopiperazine 2-OMe,5-Ph Ph 438 MeH H / / / C₂ 4-Homopiperazine 2-OMe,4-Cl,5-Me Ph 439 Me H H / / / C₂4-Homopiperazine 2-Me,4-Cl,5-CF₃ Ph 440 Me H H / / / C₂ 4-Homopiperazine5-Tetralin 441 Me H H / / / C₂ 4-Homopiperazine 4-Indan 442 Me H H / / /C₂ 4-Homopiperazine 1-Naphthalene 443 Me H H / / / C₂ 4-Homopiperazine2-OMe-1-Naphthalene 444 Me H H / / / C₂ 4-Homopiperazine2-Me-1-Naphthalene 445 Me H H / / / C₂ 4-Homopiperazine7-OMe-1-Naphthalene 446 Me H H / / / C₂ 4-Homopiperazine8-Me-1-Naphthalene 447 Me H H / / / C₂ 4-Homopiperazine 2-Quinazoline448 Me H H / / / C₂ 4-Homopiperazine 3-Indole 449 Me H H / / / C₂4-Homopiperazine 1-Phthalazine 450 Me H H / / / C₂ 4-Homopiperazine2-Quinoline 451 Me H H / / / C₂ 4-Homopiperazine 1-Isoquinoline 452 Me HH / / / C₂ 4-Homopiperazine 2-Pyrimidine 453 Me H H / / / C₂4-Homopiperazine 2-tBu,4-CF₃-6-Pyrimidine 454 Me H H / / / C₂4-Homopiperazine 2-Pyridine 455 Me H H / / / C₂ Azepan 2-Me—Ph 456 Me HH / / / C₂ Azepan Ph 457 Me H H / / / C₂ Azepan 2-OMe—Ph 458 Me H H / // C₂ Azepan 2-Cl—Ph 459 Me H H H H / C₂ Azepan 2-NR⁵R⁶Ph 460 Me H H / /Me C₂ Azepan 2-CO₂R⁷Ph 461 Me H H / / / C₂ Azepan 3-tBu Ph 462 Me H H // / C₂ Azepan 4-Ph—Ph 463 Me H H / / / C₂ Azepan 2-Me,3-Me—Ph 464 Me H H/ / / C₂ Azepan 2-Me,4-Cl,5-CF₃Ph 465 Me H H / / / C₂ Azepan 4-Tetraline466 Me H H / / / C₂ Azepan 4-Indan 467 Me H H / / / C₂ Azepan1-Naphthalene 468 Me H H / / / C₂ Azepan 2-OMe-1-Naphthalene 469 Me H H/ / / C₂ Azepan 2-Pyrimidine 470 Me H H / / / C₂ Azepan 2-Quinoline 471Me H H / / / C₂ Azepan 1-Phthalazine 472 Me H H / / / C₂ Azepan2-tBu,4-CF₃-6-Pyrimidine 473 Me H H / / / C₂ 2-Pyridine 474 Me H H / / /C₂ Azepan 4-NO₂—Ph 475 Me H H / / / C₂ Azepan 2-OH—Ph 476 Me H H / / /C₂ Tetrahydro-2H-azepine 2-Me—Ph 477 Me H H / / / C₂Tetrahydro-2H-azepine Ph 478 Me H H / / / C₂ Tetrahydro-2H-azepine2-OMe—Ph 479 Me H H / / / C₂ Tetrahydro-2H-azepine 2-Cl—Ph 480 Me H H HH / C₂ Tetrahydro-2H-azepine 2-NR⁵R⁶—Ph 481 Me H H / / Me C₂Tetrahydro-2H-azepine 2-CO₂R⁷—Ph 482 Me H H / / / C₂Tetrahydro-2H-azepine 3-tBu—Ph 483 Me H H / / / C₂ Tetrahydro-2H-azepine4-Ph—Ph 484 Me H H / / / C₂ Tetrahydro-2H-azepine 2-Me,3-Me—Ph 485 Me HH / / / C₂ Tetrahydro-2H-azepine 2-Me,4-Cl,5-CF₃Ph 486 Me H H / / / C₂Tetrahydro-2H-azepine 5-Tetraline 487 Me H H / / / C₂Tetrahydro-2H-azepine 4-Indan 488 Me H H / / / C₂ Tetrahydro-2H-azepine1-Naphthalene 489 Me H H / / / C₂ Tetrahydro-2H-azepine2-OMe-1-Naphthalene 490 Me H H / / / C₂ Tetrahydro-2H-azepine2-Pyrimidine 491 Me H H / / / C₂ Tetrahydro-2H-azepine 2-Quinoline 492Me H H / / / C₂ Tetrahydro-2H-azepine 1-Phthalazine 493 Me H H / / / C₂Tetrahydro-2H-azepine 2-tBu,4-CF₃-6-Pyrimidine 494 Me H H / / / C₂Tetrahydro-2H-azepine 2-Pyridine 495 Me H H / / / C₂Tetrahydro-2H-azepine 4-NO₂—Ph 496 Me H H / / / C₂ Tetrahydro-2H-azepine2-OH—Ph 497 Me H H / / / C₃ Piperazine 2-Me—Ph 498 Me H H / / / C₃Piperazine 2-OMe—Ph 499 Me H H H H / C₃ Piperazine 2-NR⁵R⁶—Ph 500 Me H H/ / Me C₃ Piperazine 2-CO₂R⁷—Ph 501 Me H H / / / C₃ Piperazine 3-tBu—Ph502 Me H H / / / C₃ Piperazine 2-Me,3-Me—Ph 503 Me H H / / / C₃Piperazine 5-Tetraline 504 Me H H / / / C₃ Piperazine 4-Indan 505 Me H H/ / / C₃ Piperazine 1-Naphthalene 506 Me H H / / / C₃ Piperazine2-Me-1-Naphthalene 507 Me H H / / / C₃ Piperazine 2-Pyrimidine 508 Me HH / / / C₃ Piperazine 1-Phthalazine 509 Me H H / / / C₃ Piperidine2-Me—Ph 510 Me H H / / / C₃ Piperidine 2-OMe—Ph 511 Me H H H H / C₃Piperidine 2-NR⁵R⁶—Ph 512 Me H H / / Me C₃ Piperidine 2-CO₂R⁷—Ph 513 MeH H / / / C₃ Piperidine 3-tBu—Ph 514 Me H H / / / C₃ Piperidine2-Me,3-Me—Ph 515 Me H H / / / C₃ Piperidine 5-Tetraline 516 Me H H / / /C₃ Piperidine 4-Indan 517 Me H H / / / C₃ Piperidine 1-Naphthalene 518Me H H / / / C₃ Piperidine 2-Me-1-Naphthalene 519 Me H H / / / C₃Piperidine 2-Pyrimidine 520 Me H H / / / C₃ Piperidine 1-Phthalazine 521Me H H / / / C₃ 4-Tetrahydro-1,2,3,6-pyridine 2-Me—Ph 522 Me H H / / /C₃ 4-Tetrahydro-1,2,3,6-pyridine 2-OMe—Ph 523 Me H H H H / C₃4-Tetrahydro-1,2,3,6-pyridine 2-NR⁵R⁶—Ph 524 Me H H / / Me C₃4-Tetrahydro-1,2,3,6-pyridine 2-CO₂R⁷—Ph 525 Me H H / / / C₃4-Tetrahydro-1,2,3,6-pyridine 3-tBu—Ph 526 Me H H / / / C₃4-Tetrahydro-1,2,3,6-pyridine 2-Me,3-Me—Ph 527 Me H H / / / C₃4-Tetrahydro-1,2,3,6-pyridine 5-Tetraline 528 Me H H / / / C₃4-Tetrahydro-1,2,3,6-pyridine 4-Indan 529 Me H H / / / C₃4-Tetrahydro-1,2,3,6-pyridine 1-Naphthalene 530 Me H H / / / C₃4-Tetrahydro-1,2,3,6-pyridine 2-Me-1-Naphthalene 531 Me H H / / / C₃4-Tetrahydro-1,2,3,6-pyridine 2-Pyrimidine 532 Me H H / / / C₃4-Tetrahydro-1,2,3,6-pyridine 1-Phthalazine 533 Me H H / / / C₃Homopiperazine 2-Me—Ph 534 Me H H / / / C₃ Homopiperazine 2-Me,3-Me—Ph535 Me H H / / / C₃ Homopiperazine 5-Tetraline 536 Me H H / / / C₃Homopiperazine 1-Naphthalene 537 Me H H / / / C₃ Homopiperazine2-Me-1-Naphthalene 538 Me H H / / / C₃ Homopiperazine 2-Pyrimidine 539Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine 2-Me—Ph 540 Me H H / / /CH₂—C(CH₂)—CH₂ Piperazine 2-Me,3-Me—Ph 541 Me H H / / / CH₂—C(CH₂)—CH₂Piperazine 5-Tetraline 542 Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine1-Naphthalene 543 Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine2-OMe-1-Naphthalene 544 Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine2-Pyrimidine 545 Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine 2-Quinoline 546Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine 2-Me—Ph 547 Me H H / / /CH₂—C(CH₂)—CH₂ Piperazine 2-Me,3-Me—Ph 548 Me H H / / / CH₂—C(CH₂)—CH₂Piperazine 5-Tetraline 549 Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine1-Naphthalene 550 Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine2-OMe-1-Naphthalene 551 Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine2-Pyrimidine 552 Me H H / / / CH₂—C(CH₂)—CH₂ Piperazine 2-Quinoline 553Me H H / / / CH₂—C(CH₂)—CH₂ Tetrahydropyridine 2-Me—Ph 554 Me H H / / /CH₂—C(CH₂)—CH₂ Tetrahydropyridine 2-Me,3-Me—Ph 555 Me H H / / /CH₂—C(CH₂)—CH₂ Tetrahydropyridine 5-Tetraline 556 Me H H / / /CH₂—C(CH₂)—CH₂ Tetrahydropyridine 1-Naphthalene 557 Me H H / / /CH₂—C(CH₂)—CH₂ Tetrahydropyridine 2-OMe-1-Naphthalene 558 Me H H / / /CH₂—C(CH₂)—CH₂ Tetrahydropyridine 2-Pyrimidine 559 Me H H / / /CH₂—C(CH₂)—CH₂ Tetrahydropyridine 2-Quinoline 560 Me H H / / /CH₂—C(CH₂)—CH₂ Homopiperazine 2-Me—Ph 561 Me H H / / / CH₂—C(CH₂)—CH₂Homopiperazine 2-Me,3-Me—Ph 562 Me H H / / / CH₂—C(CH₂)—CH₂Homopiperazine 5-Tetraline 563 Me H H / / / CH₂—C(CH₂)—CH₂Homopiperazine 1-Naphthalene 564 Me H H / / / CH₂—C(CH₂)—CH₂Homopiperazine 2-OMe-1-Naphthalene 565 Me H H / / / CH₂—C(CH₂)—CH₂Homopiperazine 2-Pyrimidine 566 Me H H / / / CH₂—C(CH₂)—CH₂Homopiperazine 2-Quinoline 567 Me H H / / / CH₂—CH(OH)CH₂ Piperazine2-Me—Ph 568 Me H H / / / CH₂—CH(OH)CH₂ Piperazine 2-Me,3-Me—Ph 569 Me HH / / / CH₂—CH(OH)CH₂ Piperazine 5-Tetraline 570 Me H H / / /CH₂—CH(OH)CH₂ Piperazine 1-Naphthalene 571 Me H H / / / CH₂—CH(OH)CH₂Piperazine 2-OMe-1-Naphthalene 572 Me H H / / / CH₂—CH(OH)CH₂Tetrahydropyridine 2-Pyrimidine 573 Me H H / / / CH₂—CH(OH)CH₂Homopiperazine 2-Quinoline 574 Me H H / / / C₂—N(Me)—C₂ Piperazine2-Me—Ph 575 Me H H / / / C₂—N(Me)—C₂ Piperazine 2-Me,3-Me—Ph 576 Me H H/ / / C₂—N(Me)—C₂ Piperazine 5-Tetraline 577 Me H H / / / C₂—N(Me)—C₂Piperazine 1-Naphthalene 578 Me H H / / / C₂—N(Me)—C₂ Piperazine2-OMe-1-Naphthalene 579 Me H H / / / C₂—N(Me)—C₂ Tetrahydropyridine2-Pyrimidine 580 Me H H / / / C₂—N(Me)—C₂ Homopiperazine 2-Quinoline 581Me H H / / / CH₂CH(CH₃)—CH₂ Piperazine 5-Tetralin 582 Me H H / / /CH₂CH(CH₃)—CH₂ Piperazine 1-Naphthalene 583 Me H H / / / CH₂CH(CH₃)—CH₂Piperazine 2-Me,3-Me—Ph 584 Me H H / / / CH₂CH(CH₃)—CH₂Tetrahydropyridine 2-Pyrimidine 585 Me H H / / / CH₂CH(CH₃)—CH₂Homopiperazine 2-OMe-Naphthalene 586 Me H H / / / C₈ Piperazine5-Tetralin 587 Me H H / / / C₈ Piperazine 1-Naphthalene 588 Me H H / / /C₈ Piperidine 2-Me,3-Me—Ph 589 Me H H / / / C₈ Tetrahydropyridine2-Pyrimidine 590 Me H H / / / C₈ Homopiperazine 2-OMe-Naphthalene 591 Me5-Me H / / / C₂ Piperazine 5-Tetralin 592 Me 5-Me H / / / C₂ Piperazine1-Naphthalene 593 Me 5-Me H / / / C₂ Piperazine 2-OMe—Ph 594 Me 5-Me H // / C₂ Piperazine 2-Pyrimidine 595 Me 5-Me H / / / C₂ Piperazine2-OMe-Naphthalene 596 Me 5-Me H / / / C₂ Piperidine 2-Me,3-Me—Ph 597 Me5-Me H / / / C₂ Tetrahydropyridine 2-Quinoline 598 Me 5-Me H / / / C₂Homopiperazine 2-Cl—Ph 599 Me 5-Me H / / / C₃ Piperazine 5-Tetralin 600Me 5-Me H / / / C₃ Piperazine 1-Naphthalene 601 Me 5-Me H / / / C₃Piperidine 2-Pyrimidine 602 Me 5-Me H / / / C₃ Tetrahydropyridine2-Me,3Me Ph 603 Me 5-Me H / / / C₃ Homopiperazine 2-OMe-Naphthalene 604Me 4-Cl H / / / C₂ Piperazine 1-Naphthalene 605 Me 5-OH H / / / C₂Piperazine 1-Naphthalene 606 Me 6-OMe H / / / C₂ Piperazine1-Naphthalene 607 Me 4-F H / / / C₂ Piperazine 1-Naphthalene 608 Me6-OMe H / / / C₂ Piperazine 1-Naphthalene 609 Me 4-CF₃ H / / H C₂Piperazine 1-Naphthalene 610 Me 6-CO₂R⁷ H / / Me C₂ Piperazine1-Naphthalene 611 Me 6-CO₂R⁷ H / / / C₂ Piperazine 1-Naphthalene 612 Me6-NO₂ H / / / C₂ Piperazine 1-Naphthalene 613 Me 4-CN H / / / C₂Piperazine 1-Naphthalene 614 Me 6-Pyrrol H / / / C₂ Piperazine1-Naphthalene 615 Me 4(-C₂—Ph) H / / / C₂ Piperazine 1-Naphthalene 616Me 4[-C₄—(4-Cl)Ph] H / / / C₂ Piperazine 1-Naphthalene 617 Me4[-C₂—(2-OMe)Ph] H / / / C₂ Piperazine 1-Naphthalene 618 Me4[C₂—(3-CF₂)Ph] H / / / C₂ Piperazine 1-Naphthalene 619 Me4[C₂—(2-Me)Ph] H / / / C₂ Piperazine 1-Naphthalene 620 Me4[C₂—(2-NH₂)Ph] H / / / C₂ Piperazine 1-Naphthalene 621 Me4[C₂—(4-NO₂)Ph] H / / / C₂ Piperazine 1-Naphthalene 622 Me4[C₂—(4-OH)Ph] H / / / C₂ Piperazine 1-Naphthalene 623 Me 6-NR⁵R⁶ H Me H/ C₂ Piperazine 1-Naphthalene 624 Me 6-NR⁵R⁶ H CO Ph H / C₂ Piperazine1-Naphthalene 625 Me 6-NR⁵R⁶ H CO Me H / C₂ Piperazine 1-Naphthalene 626Me 6-NR⁵R⁶ H CO₂tBu H / C₂ Piperazine 1-Naphthalene 627 Me 6-NR⁵R⁶ H H H/ C₂ Piperazine 1-Naphthalene 628 Me 6-NR⁵R⁶ H Piperazine / C₂Piperazine 1-Naphthalene 629 Me 6-NR⁵R⁶ H Me H / C₃ Piperazine5-Tetralin 630 Me 6-NR⁵R⁶ H CO Ph H / C₃ Piperazine 5-Tetralin 631 Me6-NR⁵R⁶ H CO Me H / C₃ Piperazine 5-Tetralin 632 Me 6-NR⁵R⁶ H / / / C₃Piperazine 5-Tetralin 633 Me 6-Pyrrol H / / / C₃ Piperazine 5-Tetralin634 Me 6-NO₂ H / / / C₃ Piperazine 5-Tetralin 635 Et H H / / / C₂Piperazine 1-Naphthalene 636 Et H H / / / C₂ Piperazine 2-OMe—Ph 637 EtH H / / / C₂ Piperazine 2-Pyrimidine 638 Et H H / / / C₂ Piperazine2-OMe-1-Naphthalene 639 Et H H / / / C₂ Piperazine 2-Me,3-Me—Ph

We claim:
 1. A 2-substituted 1,2-benzoisothiazole derivative of theformula I

where R¹ and R² are, independently of one another, (C₁₋₆) alkyl, R³, R⁴are, independently of one another, hydrogen, (C₁₋₆) alkyl branched orunbranched, OH, O—(C₁₋₆)-alkyl branched or unbranched, F, Cl, Br, I,trifluoromethyl, NR⁵R⁶, CO₂R⁷, nitro, cyano, pyrrole, a phenylalkylC₁-C₄ radical which in turn can be substituted on the aromatic system byF, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, hydroxyl,amino, cyano or nitro, R⁵ and R⁶ are, independently of one another,hydrogen, (C₁₋₆) alkyl branched or unbranched, COPh, CO₂tBu,CO—(C₁₋₄)-alkyl or together are a 5- or 6-membered ring which maycontain a second nitrogen, R⁷ is hydrogen or (C₁₋₆) alkyl branched orunbranched, A is branched or unbranched (C₁₋₁₀)-alkylene orstraight-chain or branched (C₂₋₁₀)-alkylene which contains one or moregroups Z selected from O, S, NR⁷, cyclopropyl, CHOH, a double or atriple bond, B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine,4-piperazine and homopiperazine, the linkage to A taking place by onenitrogen atom of B, and Ar is phenyl which is unsubstituted orsubstituted by (C₁₋₆) alkyl branched or unbranched, O—(C₁₋₆)-alkylbranched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR⁵R⁶, CO₂R⁷,cyano or phenyl or is tetralin, indan, a fused aromatic system selectedfrom the group consisting of naphthyl which is unsubstituted orsubstituted by (C₁₋₄) alkyl or O(C₁₋₄) alkyl, anthracene and 5- or6-membered aromatic heterocycles having 1 or 2 nitrogen atoms which maybe substituted by methyl and/or trifluoromethyl and which may also befused to other aromatic radicals, its possible enantiomers anddiastereomers, tautomeric forms and its salts with physiologicallytolerated acids.
 2. A 2-substituted 1,2-benzoisothiazole derivative asclaimed in claim 1, where R¹ and R² are (C₁₋₂) alkyl, R³ and R⁴ are,independently of one another, hydrogen, O—(C₁₋₄)-alkyl branched orunbranched, F, Cl, Br, trifluoromethyl, NR⁵R⁶, nitro, cyano and phenyl,R⁵ and R⁶ are, independently of one another, hydrogen, COPh, CO₂tBu,(C₁₋₆) alkyl branched or unbranched and CO—(C₁₋₄)-alkyl, A is branchedor unbranched (C₂₋₅) alkylene or straight-chain or branched (C₂₋₅)alkylene which contains a group Z which is selected from CHOH,cyclopropyl, a double or a triple bond, B is 4-piperidin-1-yl,4-tetrahydro-1,2,3,6-pyridin-1-yl, 4-piperazin-1-yl or4-(1,4-diazepin-1-yl), and Ar is phenyl which is unsubstituted orsubstituted by (C₁₋₆) alkyl branched or unbranched, O—(C₁₋₆)-alkylbranched or unbranched, F, Cl, trifluoromethyl, NR⁵R⁶, CO₂R⁷, cyano andphenyl, or tetralin, indan, naphthyl which is unsubstituted orsubstituted by (C₁₋₄) alkyl or O(C₁₋₄) alkyl, or 6-membered aromaticheterocycles having 1 or 2 nitrogen atoms and which may also be fused toother aromatic radicals.
 3. A 2-substituted 1,2-benzoisothiazolederivative as claimed in claim 1, where R¹ and R² are methyl, R³ and R⁴are, independently of one another, hydrogen, nitro, Cl or NR⁵R⁶, R⁵ andR⁶ are, independently of one another, hydrogen, COPh andCO—(C₁₋₂)-alkyl, A is (C₂₋₃) alkylene, B is selected from the groupconsisting of 4-piperidin-1-yl, 4-piperazin-1-yl and4-tetrahydro-1,2,3,6-pyridin-1-yl, and Ar is phenyl which isunsubstituted or substituted by (C₁₋₂) alkyl or O(C₁₋₂)alkyl in position2 and 3, or tetralin, indan or naphthalene which is unsubstituted orsubstituted by (C₁₋₂)alkyl or O(C₁₋₂) alkyl, or pyridine, pyrimidine andisoquinoline.
 4. A pharmaceutical composition which is a selective5HT_(1B) and 5HT_(1A) antagonist comprising as active ingredient acompound as claimed in claim
 1. 5. The 2-substituted1,2-benzoisothiazole derivative of claim 1, wherein A is branched orunbranched (C₂₋₅)-alkylene or straight-chain or branched (C₂₋₅)-alkylenewhich contains one or more groups Z selected from cyclopropyl, CHOH anda double or triple bond.
 6. A method of treating depression in a subjectrequiring such treatment which comprises administering an effectiveamount of the composition of claim
 4. 7. A method of treating depressionand related disorders in a subject requiring such treatment whichcomprises administering an effective amount of the composition of claim4.